6-Biphenylmethyl-3-hydroxypyrimidine-2,4-diones potently and selectively inhibited HIV reverse transcriptase-associated RNase H

Eur J Med Chem. 2018 Aug 5:156:680-691. doi: 10.1016/j.ejmech.2018.07.035. Epub 2018 Jul 17.

Abstract

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains an unvalidated drug target. Reported HIV RNase H inhibitors generally lack significant antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-biphenylmethyl subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays, analogues of this new subtype potently inhibited RT RNase H in low nanomolar range without inhibiting RT polymerase (pol) or integrase strand transfer (INST) at the highest concentrations tested. In cell-based assays, a few analogues inhibited HIV in low micromolar range without cytotoxicity at concentrations up to 100 μM.

Keywords: 3-Hydroxypyrimidine-2,4-dione (HPD); Human immunodeficiency virus (HIV); Inhibitors; RNase H; Structure-activity-relationship (SAR).

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Catalytic Domain / drug effects
  • Cell Line
  • Drug Design
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Humans
  • Methylation
  • Models, Molecular
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacology*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
  • Ribonuclease H, Human Immunodeficiency Virus / chemistry
  • Ribonuclease H, Human Immunodeficiency Virus / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Pyrimidinones
  • Reverse Transcriptase Inhibitors
  • Ribonuclease H, Human Immunodeficiency Virus